Profiling of MicroRNAs and IL-10 expression in intestinal CD4+ T cells following infection with Helicobacter hepaticus

In the Helicobacter hepaticus (Hh) colitis model, Hh infection of either wild-type mice treated with a blocking antibody to the IL-10 receptor (anti-IL-10R) or IL-10 KO mice results in intestinal inflammation associated with inflammatory Th1 and Th17 responses. Recent findings suggest that altered expression of the post-transcriptional gene regulators microRNAs contribute to pathogenic immune responses during intestinal inflammation. Here, examination of microRNA expression during Hh colitis showed that microRNAs are differentially expressed in the inflamed large intestine of Hh+ IL-10 KO mice compared to uninfected controls, both at the tissue-level and the CD4+ T-cell level. Kinetic examination of the cecal and colonic levels of miR-155, miR-326 and miR-132 (microRNAs previously shown to augment Th1 and/or Th17 responses) demonstrated that miR-155 was up-regulated and miR-326 and miR-132 were down-regulated at different time points post Hh infection. Furthermore, the change in expression of these microRNAs coincided with inflammation development. Microarray profiling of large intestine LP CD4+ T cells revealed that two microRNAs were significantly up-regulated (miR-21a and miR-31) and seven microRNAs were significantly down-regulated (miR-125a, miR-125b, miR-139, miR-181a, miR-192, miR-30a and miR-467c) in colitic IL-10 KO mice compared to uninfected controls. The anti-inflammatory cytokine IL-10 is necessary for protection against intestinal inflammation. Here, the phenotype of IL-10-producing LP CD4+ T cells was examined in a non-inflammatory immune response (Hh+ WT mice) and in an inflammatory immune response (Hh+/anti-IL-10R-treated WT mice). Compared to uninfected controls, the Hh+ mice showed a slight expansion in IL-10+ IL-17A+FoxP3+/- cells whereas the Hh+/anti-IL-10R-treated mice showed a significant expansion in all the IL-10+ LP CD4+ T cells co-expressed both inflammatory cytokines IL-17A and/or IFN-γ and/or the Treg transcription factor FoxP3. The experiments carried out in this thesis demonstrate that the profile of two important regulatory factors, microRNAs and IL-10, is markedly different in LP CD4+ T cells from the colitic setting compared to uninfected controls

Tbet or Continued RORγt Expression Is Not Required for Th17-Associated Immunopathology

The discovery of Th17 cell plasticity, in which CD4 + IL-17-producing Th17 cells give rise to IL-17/IFN-γ double-producing cells and Th1-like IFNγ+ ex-Th17 lymphocytes, has raised questions regarding which of these cell types contribute to immunopathology during inflammatory diseases. In this study, we show using Helicobacter hepaticus-induced intestinal inflammation that IL-17ACre- or Rag1Cre-mediated deletion of Tbx21 has no effect on the generation of IL-17/IFN-g double-producing cells, but leads to a marked absence of Th1-like IFNγ+ ex-Th17 cells. Despite the lack of Th1-like ex-Th17 cells, the degree of H. hepaticus-Triggered intestinal inflammation in mice in which Tbx21 was excised in IL-17-producing or Rag1-expressing cells is indistinguishable from that observed in control mice. In stark contrast, using experimental autoimmune encephalomyelitis, we show that IL-17ACre-mediated deletion of Tbx21 prevents the conversion of Th17 cells to IL-17A/IFN-γ double-producing cells as well as Th1-like IFN-γ+ ex-Th17 cells. However, IL-17ACre-mediated deletion of Tbx21 has only limited effects on disease course in this model and is not compensated by Ag-specific Th1 cells. IL-17ACre-mediated deletion of Rorc reveals that RORγt is essential for the maintenance of the Th17 cell lineage, but not immunopathology during experimental autoimmune encephalomyelitis. These results show that neither the single Th17 subset, nor its progeny, is solely responsible for immunopathology or autoimmunity

Adaptive from Innate: Human IFN-γ+CD4+ T Cells Can Arise Directly from CXCL8-Producing Recent Thymic Emigrants in Babies and Adults.

We recently demonstrated that the major effector function of neonatal CD4+ T cells is to produce CXCL8, a prototypic cytokine of innate immune cells. In this article, we show that CXCL8 expression, prior to proliferation, is common in newly arising T cells (so-called "recent thymic emigrants") in adults, as well as in babies. This effector potential is acquired in the human thymus, prior to TCR signaling, but rather than describing end-stage differentiation, such cells, whether isolated from neonates or adults, can further differentiate into IFN-γ-producing CD4+ T cells. Thus, the temporal transition of host defense from innate to adaptive immunity is unexpectedly mirrored at the cellular level by the capacity of human innate-like CXCL8-producing CD4+ T cells to transition directly into Th1 cells

Global patterns of antigen receptor repertoire disruption across adaptive immune compartments in COVID-19

Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) β and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2–specific seroconversion, and enrichment of some shared SARS-CoV-2–associated sequences. No significant age-related or disease severity–related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRβ and TCRδ loci, including some TCRβ sequence–sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection

Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care